One step away from Diabetes Cell therapy: details
Diabetes and stem cells
Alexandra Bruter, <url>
A group of American scientists published in the journal Cell a paper describing a method for obtaining insulin–producing cells from pluripotent stem cells - Pagliuca et al., Generation of Functional Human Pancreatic b Cells In Vitro Generation of Functional Human Pancreatic b Cells In Vitro (press release “From stem cells to billions of human insulin-producing cells” is published on the website of the Harvard Stem Cell Institute – VM). The method does not involve genetic modification of cells and is therefore safe. All stages of differentiation took place simply under the influence of molecules added to the medium. Experiments have already been carried out confirming that cells with the required properties and capable of secreting the right amount of insulin into the blood plasma have actually turned out.
In order for cell transplantation to have a therapeutic effect, there must be a lot of cells. Of course, it is almost impossible to make differentiated cells multiply noticeably. Therefore, stem cells, which can multiply quite quickly and for a long time, and then differentiate into cells of the right type, are an indispensable source of cells for potential therapy. Animal experiments have already shown, for example, that the heart muscle cells obtained in this way helped with arrhythmia, neuron progenitor cells helped recovery after spinal cord injury, and retinal epithelial cells helped improve vision in age-related macular degeneration.
Diabetes from an epidemiological and economic point of view is much more dangerous than macular degeneration. More than 300 million people are sick all over the world, among them, by the way, two children of one of the authors of the work. But it is quite difficult to get insulin-producing cells.
Insulin is produced by beta cells of the islets of Langerhans in the pancreas. In addition to beta cells, there are also alpha cells in the islets that secrete glucagon, an insulin antagonist: somewhat simplifying, we can say that insulin transmits a signal to muscle cells, adipose tissue and others to absorb glucose from the bloodstream, and glucagon, on the contrary, causes liver cells to convert stored glycogen into glucose and release into the blood. Therefore, it is very important that beta cells, not alpha cells, are formed during the differentiation of stem cells prior to transplantation.
A natural question arises why it is impossible to take the first available cells, inject the insulin gene into them, and let them produce them. This does not work for many reasons: the synthesis, maturation and secretion of insulin is a complex multi–stage process that requires the participation of many factors. Firstly, insulin secretion should occur in limited quantities and only in response to the intake of glucose or other food into the body. A short-term elevated glucose level for a person does not pose a serious danger, for the development of diabetes symptoms, a noticeable excess is needed for some time. But low glucose concentration and hypoglycemia associated with it are dangerous conditions, fraught with almost sudden loss of consciousness, coma and other troubles in a person who just felt quite well. I went to bed, for example, of course, I didn't eat anything in my sleep, excess insulin led to a strong decrease in glucose levels, and I can't wake up myself anymore. In beta cells, a special system ensures that insulin enters the blood only in response to an increase in glucose levels. Other cells cannot do without such a system, it is simply dangerous.
Another problem is that the original protein molecule of the insulin precursor preproinsulin consists of 110 amino acids, and the finished functional insulin consists of 31. In the process of maturation, special enzymes are cut off piece by piece. These enzymes are active only in beta cells.
Genetic engineering, however, offers ways to circumvent this problem: in the gene encoding insulin, several nucleotides can be replaced so that the cutting sites with specific beta-cell enzymes are replaced by sites that can be cut by enzymes in any cell. But the problem of precise glucose-dependent secretion is still being solved with great difficulty.
For the treatment of type I diabetes, cadaveric beta cell transplantation is sometimes performed, but the cells in this case are few in number, and this is followed by all the problems associated with immunosuppression, since the cells are foreign. However, in this way it has already been possible to achieve the abolition of insulin for a period of five years. But this method cannot become large-scale.
That is why it is important to get cells that are as similar as possible to beta cells. This is what the authors of the work managed to do thanks to the six-step method they developed.
Diagram from the article in Cell – VM
The whole process takes about a month. Cells from pluripotent stem cells gradually become more differentiated, different factors at each stage direct differentiation in the right direction. The resulting cells were transplanted into mice with type I diabetes and coped well with maintaining blood glucose levels at normal levels. The method is quite effective. When it comes to clinical trials, the authors hope that they will be able to transplant 150 million cells to each patient. The last stage of preclinical testing is currently underway, including on primates.
A separate question is how to protect new cells from the attack of the immune system. After all, type I diabetes develops precisely because the cells of the immune system make mistakes, taking beta cells for enemies and killing them. Work is also underway to solve this problem, and some progress has already been made.
Portal "Eternal youth" http://vechnayamolodost.ru15.10.2014